New hope for Shar-Pei... coming soon

There is news today about a long-awaited DNA test for Shar-Pei that could revolutionise the health of the breed - as long as breeders are willing to accept less-wrinkled dogs.

Shar-Pei expert Dr Linda Tintle confirms on her Facebook page that a new test has been validated  - but warns breeders and puppy-buyers that, for the sake of the health of their dogs, they may have to learn to love the breed without the over-abundant wrinkles that are a hallmark of the breed in the West (but not a feature of the original Chinese dog).

Four years ago, Dr Tintle was part of an international team of researchers led by Mia Olssen in Sweden. The team reported some key findings - and has been working on a DNA test ever since.

• the Western "meathmouth" Shar-pei has a different version of  the hyaluron-coding gene HAS2 to its less-wrinkly original cousin (also known as the "traditional" or "bonemouth" Shar-pei) 

• the "meatmouth"mutation - when numerous copies of it are present - is linked to health issues. Geneticists call this a 'copy-number variant/variation'' or CNV. (In humans, CNVs are often associated with disease and the same phenomenon is thought to be linked to an elevated risk for cancer.)

• Although not perfectly correlated, the more wrinkled a dog is, the more likely it is to have more copies of the mutation (which figures... more copies of a gene that codes for hyaluron production is likely to result in over-production of hyaluron. It is excess hyaluron that is linked to many Shar-pei health problems.)

•  The "traditional" Shar-pei, meanwhile, has a different version of the gene and appears to be much less susceptible to the classic Shar-Pei health issues.

(You can read the 2011 paper here.)


In the West, the breed is based on a tiny number of dogs exported from China in the 1970s. Their wrinkly puppy faces were an instant hit and they were bred (and inbred) profligately to meet the demand. The more wrinkles the better... which led to the selection and breeding of ever-more wrinkled dogs - to the extent that in some parts of the world today you can find poor creatures like this (this dog is in Uzbekistan).

You are much less likely to find such extremes being produced by breeders in the US/UK - but, nevertheless, you still see some very padded dogs in the show-ring and many Shar-pei puppies have to have their eyes 'tacked' to prevent their rolled-in eyelashes ulcerating their eyes.  No doubt too that there are many breeders (not all pile-em-high pet breeders) still selling these dogs by the wrinkle. Some adult dogs' eyes are so obliterated by rolls of flesh that facelifts have to be done to save their sight.

Even when they are not as horribly-wrinkled as the Uzbekistan dog above, the modern Shar-pei's health problems are rife.  Excess hyaluron builds up in the dog's body prompting an inflammatory response that manifests itself in a number of clinical signs, ranging from unpleasant to life-threatening.

• Familial Shar-pei Fever - sudden agonising fevers during which the dogs can barely move
• Amyloidosis - leading to kidney/liver failure
• Arthritis - immune mediated
• Recurrent otitis - ear infections (not helped by the selection in the breed for tiny ears/ear canals which hinder air-flow)
• Hereditary Cutaneous Hyaluronosis - or mucinosis as it is sometimes called.

Yes, it's that disgusting...

The above conditions are now lumped under the umbrella of SPAID (Shar-Pei Auto Inflammatory Disease) - with a number of other symptoms also thought to be linked, including Inflammatory Bowel Disease (IBD), allergic dermatitis, streptococcal toxic shock syndrome/necrotising fascitis (yep, that flesh-eating bug), lymphedema and Swollen Hock Syndrome.

My view has always been that the Western Shar-pei is such a genetic/medical basket case that it is unethical to breed it.   But the new DNA test should be a help, just as long as breeders are willing to use it and just as long as it does finally make it to market.

The test will reveal not just that a Shar-Pei carries the meatmouth mutation but, critically, how many copies of the mutation it has, allowing breeders to choose to breed from those with fewer copies. (Again, the lower the number of repeats, the less likely the dog is to suffer from hyaluronosis. As these are also likely to be less phenothypically extreme dogs, it should over time lead to more moderate dogs).

Well there's the hope, anyway. And the DNA test is taking an age. The reason for the hold-up is unknown, but likely due to scientific and commercial manoeuvrings . It is hopefully not due to a challenge published in Animal Genetics last year by a team in Hanover which asserted that the 2011 findings were flawed.

Certainly, there has been a very robust response from Linda Tintle's team (reproduced in full below for those interested*). Given the stature of the scientists involved in the original study (they include canine genetics royalty Kerstin Lindblad-Toh), I know who my money is on.

I am also encouraged that there is more interest in the  traditional dog, which common-sense tells you is sounder than the overdone Western version.  There are now some trad dogs in the UK - and below is the stunning Maxim, owned by Kikka Posti in Finland.  Maxim has been a great ambassador for the traditionl dog, particularly on social media.

Compare Maxim to this year's Cruft's winner - and, in particular, check out the dog below's hock area. There is a bagginess there likely due to excess hyaluron and it isn't something that - in my opinion - judges should be rewarding. (Or those posty back legs which predispose the breed to cruciate ligament tears - although it should be said that they are often a feature of the trad dog, too.)

Kennel Clubs could play their part here, too, with a class for the traditional Shar-Pei in which longer legs, less padding and only slight wrinkling won't get the dog thrown out of the ring for not being a real Shar-Pei.

(And yes, sadly that's happened...)

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*

Linda Tintle

Our collaborative veterinary and genetics team has been working tirelessly for almost ten years to dissect the genetics of what was known as Shar-Pei fever, but is now recognized as Shar-Pei Autoinflammatory Disease (SPAID). This key driver of our work has been to understand the mechanics of this disease, from genetics through to clinical presentation, with the ultimate goal of developing a reliable test with which to help the community. Together with Shar-Pei owners, we have collected samples from more than 500 individuals and with this level of personal and professional involvement, we take our reporting responsibility seriously. 

We feel in light of the recent publications that we need to clarify what we have learned about this disorder and how our scientific findings differ from that reported by others. 

In 2011 we published a paper where we described the correlation between a breed-specific genetic variant (a copy number variant) in Shar-Pei and the higher activity of one of the genes encoding hyaluronan (HAS2). The same genetic variant was also correlated to a higher risk for an individual to suffer from periodic fever (reference 1). Taken together with other studies (reference 2-4), this copy number variant also appears to underlie the folded and thickened skin of Shar-Pei, which we know is a result of increased deposition of hyaluronan in the skin. 

We followed this in 2013 with a breakthrough paper for this disease (reference 5). After the meticulous examination of veterinary medical records from 255 Shar-Pei, we realized that fever was only one of the clinical signs of inflammatory disease seen within this breed. We coined the term Shar-Pei Autoinflammatory Disease (SPAID), to cover a spectrum of inflammatory signs including fever, arthritis, ear and skin inflammation and amyloidosis. Our research showed that SPAID is one genetic locus, meaning that one region of the genome is correlated to all these clinical signs. 

We welcome the evaluation of our work by others, as reproducibility is key to scientific validation. However in order to “refute” our research, as was claimed by Metzger & Distl (2014), the same methodology in terms of techniques and disease classification must be employed. In this case, that simply was not done. Let us take you through our most important point of contention, the classification of healthy and sick Shar-Pei. 

As we illustrated above, we have invested a great deal of time and effort in order to strictly classify healthy and sick individuals prior to the commencement of genetic studies. This process involves the combination of interviews with owners and veterinarians, plus the study of each dog´s medical records. This is extremely important, as in complex diseases such as SPAID, an individual can be a carrier of the genetic risk factor without being ill. For this reason, we excluded all “healthy” dogs with sick relatives. We also excluded “healthy” individuals with vague or more mild signs of inflammation, such as a reluctance to move for one or two days as this observation can be easy to miss or interpret as something else, while it is in fact disease symptoms. On top of this, we required “healthy” individuals to be five years of age or older. This was to avoid the misclassification of dogs that had a later onset of fever events as “healthy”. 

These are just three examples of our very careful approach to ensuring healthy and sick dogs were properly characterized before studying what differentiated them on a genetic level and is in clear contrast to Metzger & Distl who state only “47% of the analyzed Shar-Pei dogs were older than 3 years at the time of investigation". It is likely that “silent carriers” or dogs with a later disease onset were classified as healthy in their investigation and this could be a possible explanation as to why they failed to see a correlation between disease and genetic variant. 

Our research has shown that we are not dealing with a single clinical symptom, but rather the syndrome of SPAID. This means that the genetic test we developed needs to be evaluated for understanding not only Familial Shar-Pei Fever, but rather a raft of inflammatory conditions. We are finalizing our results using a new technology that offers greater precision in measuring the copy number variants in each individual. This technique has greatly increased our understanding of how variants are passed down from parent to offspring over generations of breeding. 

With help from engaged and generous dog owners world-wide, we have been able to replicate our results in more than 200 Shar-Pei dogs and are confident that our results hold and will be useful for the breed’s health. 

Jennifer Meadows, Ph.D.
Dept. Medical Biochemistry & Microbiology (IMBIM)
Uppsala University, Uppsala, Sweden

Kerstin Lindblad-Toh, Ph.D.
Professor in Comparative Genomics, Uppsala University, Sweden
Co-director of Science for Life Laboratory, Uppsala, Sweden
Scientific Director of Vertebrate Genome Biology, Broad Institute, USA.

Mia Olsson, Ph.D.
Faculty of medicine, Department of Pediatrics
University of British Columbia, Vancouver, Canada

Linda J.M. Tintle, D.V.M.
Wurtsboro Veterinary Clinic, P.C.
Wurtsboro, New York, USA

Åke Hedhammar, D.V.M., M.Sc., Ph.D., Dipl. Internal Medicine-Companion Animals
Senior Professor, Department of Clinical Sciences
Swedish University of Agricultural Sciences
Uppsala, Sweden

References:
1. Novel unstable duplication upstream of HAS2 predisposes to a breed-defining skin phenotype and a periodic fever syndrome in Chinese Shar-Pei dogs. Olsson M, Meadows JRS, Truve K, et al. PLOS Genetics 7: e1001332, 2011.
2. Cutaneous mucinosis in shar-pei dogs is due to hyaluronic acid deposition and is associated with high levels of hyaluronic acid in serum. Zanna G, Fondevila D, Bardagí M, et al. Vet Dermatol 19; 5, 314–318, 2008.
3. Hereditary cutaneous mucinosis in shar pei dogs is associated with increased hyaluronan synthase-2 mRNA transcription by cultured dermal fibroblasts. Zanna G, Docampo MJ, Fondevila D, et al. Vet Dermatol 20(5-6):377-82, 2009.
4. Increased HAS2-driven hyaluronic acid synthesis in shar-pei dogs with hereditary cutaneous hyaluronosis (mucinosis). Docampo MJ, Zanna G, Fondevila D, et al. Vet Dermatol 22; 535-545, 2011.
5. Thorough investigation of a canine autoinflammatory disease (AID) confirms one main risk locus and suggests a modifier locus for amyloidosis. Olsson M, Tintle L, Kierczak M, et al. PLOS ONE 8:e75242, 2013.